An important part of the recent explosion of research in peptide chemistry and the effect of protein hormones on all life forms has been research in growth hormone. The study of the production of growth hormone in various animals has revealed that a relatively small peptide known as growth hormone releasing factor has a major role in the production and secretion of growth hormone in all the species which have been studied. Interestingly, endogenous growth hormone releasing factor (GRF), is a very similar peptide in all of the species whose GRF has been sequenced. It is a peptide of 43 or 44 amino acids in all known species, and the acid terminal of the peptide is amidated in all known species except the rat. The sequence of amino acids in the various endogenous GRF's is quite similar; indeed, bovine GRF is identical to caprine GRF.
The following nomenclature is used in this document. The term "growth hormone releasing factor" (GRF) is used broadly to refer to any peptide which functions to increase the production and release of growth hormone in an economic mammal. The term "endogenous GRF" is used to refer to GRF naturally produced by an animal. In referring to synthetically or recombinantly produced GRF's, an initial is used to indicate the species whose GRF has been duplicated; e.g., "h" for human, "b" for bovine, etc. When a GRF is the acid form, the fact is stated; it is amidated otherwise. The term "analog" is used to refer to peptides which function as GRF's, but have less amino acids than the endogenous GRF, or a different sequence. Synthetic GRF's containing less amino acids than the endogenous GRF are indicated by a number; e.g. "hGRF29" indicates a GRF made up of the first 29 amino acids of human endogenous GRF.
The benefit of increasing the growth hormone level in an economic mammal is now well established. The most conspicuous known benefit is the increase in milk production by a dairy cow when growth hormone is increased. Improved growth rates and feed efficiency by pigs and sheep having increased growth hormone levels have been reported in the literature. The same beneficial effects have not yet been reported in cattle, but it must be realized that growth hormone and GRF are still scarce and expensive, and it is believed that no cattle feeding trials with either agent have yet been done. For some years the growth rate of abnormally small children has been increased by direct administration of growth hormone, at great expense because of the difficulty of obtaining the hormone, and no comparable amount of study has as yet been devoted to the use of growth hormone in economic mammals.
The most extensively studied GRF, of course, is the human. It has been found that the endogenous human GRF peptide can be extensively modified without destroying its effectiveness in increasing the production and secretion of growth hormone. Human GRF analogs of 23 to 40 amino acids have been made, in both the amidated and acid-terminated forms, and found to be active. Further, various changes have been made in the endogenous peptide, such as the interchange of histidine, 3-methylhistidine or N-acetyltyrosine in place of tyrosine at the 1-position of the peptide. Those substances are also effective.
It is perhaps not surprising, in view of the similarity of the endogenous GRF's of different species, that they typically are effective across species. For example, Kraft et al., Domestic Animal Endocrinology 2, 133-39 (1985) showed that endogenous human GRF and a human GRF analog having 40 amino acids and a free acid terminal (hGRF40 acid) were active in rats, Rhesus monkeys, rabbits, sheep, cattle and chickens, as well as in humans.
In the human, it appears that GRF is produced both by pancreatic tumors and by the hypothalamus. Identical peptides are produced by both organs. The earliest GRF work was done with peptide produced by human pancreatic tumors, but it has now been clearly shown that the normal pancreas, as well as the hypothalamus, produces the same peptide, which is endogenous human GRF.
There is an extensive literature on GRF and its relationship with the production and secretion of growth hormone. The following articles are mentioned as giving an overview, and an entry into the literature.
Ling et al., Ann. Rev. Biochem. 54, 403-23 (1985)
Baird et al., Neuroendocrinoloqy 42, 273-76 (1986)
Kensinger et al., Fed. Proc. 45, 280 (1986)
Wehrenberg et al., Endocrinology 114, 1613-16 (1984)
It has been found that, in many situations, the administration of estrogens to animals also produces an increase in endogenous growth hormone concentration. For example, Frantz et al., J. Clin. Endocr. 25, 1470-80 (1965), found that the administration of large doses of diethylstilbestrol to normal men increased growth hormone concentration, measured with the patients fasting. Trenkle, J. An. Sci. 31, 389-93 (1970), observed increased growth hormone in steers which were fed a conventional finishing diet with the addition of 10 mg/head/day of stilbestrol.
Ethinyl estradiol or "conjugated estrogens" were administered intravenously to normal men by Wiedemann et al., J. Clin. Endocr. and Metab. 42, 942-52 (1976). The authors observed a significant increase in growth hormone in 5 of 6 patients.
Thus, in general, physiologists are aware that the administration of estrogens to animals increases or tends to increase the animals' concentration of growth hormone.